Module 4 Flashcards
(163 cards)
1
Q
the development of drugs to treat infections is based on
A
selective toxicity
2
Q
selective toxicity
A
use of drugs to harm and invading organism without harming the host
3
Q
What is an antibiotic?
A
- a chemical substance that suppresses bacterial growth and may eventually destroy them
- purpose is to stop bacterial infection
4
Q
how does antibiotics stop bacterial infection
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accomplished through bacteriostatic or bactericidal effects
5
Q
Bacteriostatic
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inhibits growth and reproduction of bacteria
6
Q
Bactericidal
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directly kills bacteria
7
Q
Structure of Bacterial Cells
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have a rigid outer layer called the cell wall, completely surrounding the cytoplasmic membrane
8
Q
cell wall contains
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peptidoglycan layer, which is a complex of cross-linked polymer of polysaccharides and polypeptides
9
Q
cross-links give the cell wall
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structual rigidity and are responsible for maintaining the cells shape and integrity, preventing cell lysis from high osmotic pressure
10
Q
Gram Positive:
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thick peptidoglycan layer and no outer membrane
11
Q
Gram Negative:
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thin peptidoglycan layer and an outer membrane
12
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Narrow Spectrum:
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- only useful against particular species of microorganisms
- ex. Penicillin G primarily effective against Gram-Positive bacteria
13
Q
Broad Spectrum:
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- effective against a wider range of microorganisms, including both gram-positive and gram-negative bacteria
- ex is tetracylines
14
Q
—> Classification of Antibiotics by Biochemical Pathway
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- based on biochemical pathway targeted in the bacterial cell
- antibiotics use selecrtive toxicity by targeting and interfering with essential components of biochemical reactions, killing the bacteria
15
Q
Four groups to classify antibiotics by the biochemical pathway
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- Cell wall Synthesis Inhibitors
- Protein Synthesis Inhibitors
- DNA Synethsis Inhibitors
- Metabolic Inhibitors
16
Q
Cell wall Synthesis Inhibitors
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- function to stop the proper formation of bacterial cell wall and/or membrane, influencing structural integrity
- 2 classes: Penicillins and cephalosporins
17
Q
Protein Synthesis Inhibitors
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- inhibit protein translation within the bacteria and thereby protein synthesis
- 2 classes: tetracylines and macrolides
18
Q
DNA Synethsis Inhibitors
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- inhibit DNA replication in bacteria, preventing bacterial growth
- 1 class: flurorquinolones
19
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Metabolic Inhibitors
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- block the formation of key bacterial metabolic substrates needed for bacteria to survive and reproduce
- 1 class: antifolate
20
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Penicillins
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- Natural (Penicillin G)
- Semisynthetic (Modified versions of Penicillin G)
21
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Penicillin G
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- extracted and purified from penicillin mould
- narrow spectrum antibiotic that destroys mainlt gram-positive bacteria
22
Q
penicillin g is useful for treating
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pneumonia, middle ear infection, skin infections, syphyllis and meningitis
23
Q
Methicillin
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- organisms can produce penicillinase (an enzyme that breaks down penicillin) and become resistant to penicillin G, therefore methicillin is an antibiotic resistant to attack by penicillinase
24
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Ampicillin and Amoxicillin
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- antibiotucs that have a broader spectrum of antibacterial activity than penicillin G
-useful against a range of infections caused by gram-negative bacteria (UTI’s)
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Amoxicillin and cavulanic acid
- combination of a semisynthetic penicillin plus and inhibitor of penicillinase
- introduced into therapy to combat penicillinase-producing strains of bacteria
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What does penicillin do
interferes with cell wall formation and resulting cells are formed without walls
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bacterial cells without walls
protoplasts; fragile and ready to burst
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why are human cells unaffected by penicillin
dont have cell walls
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D alanine
a chemical component necessary for formation of new bacterial cell walls
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Adverse effects of penicillin
- most common is gastrointestinal distress due to disturbance of healthy gut flora
- allergy (1-10% population)
-rarely experience difficulty breathing and marked fall in BP
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penicillin allergy
common
-if a person is allergic to one penicillin preparation, they may be allergic to other penicilllin preparations
-rash, fever, face and tongue swelling and itchy hives
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cell wall synthesis inhibitor: Cephalosporins
- chemically similar to penicillins
-more resistant to pellicinase
-divided into 5 generations, depending on spectrum of activity
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Adverse effects of Cephalosporins
- similar to penicillin
-GI side effects such as nausea and diarrhea
-potential but uncommon to be allergic to cephalosporins and penicillin
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penicillin and cephalosporins Mechanism of action
compete with D-alanine on transpeptidase, inhibiting the enzyme, therefore cell wall is dysfunctional
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fluoroquinolones
chemically distinct class of antibiotics that inhibit bacterial DNA synthesis
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example of class of fluoroquinolones
Ciprofloxacin
-can be used for oral or IV therapy of injections cause by variety Gram-positive and Gram-negative microorganism
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Tetracyclines
- one of first broad spectrum antibiotics developed
- because of widespread use for many years, many bacteria have become resistant
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mechanism of action tetracyclines
bind to 30S subunit of mRNA-rbosome complex and prevent addiction of amino acids to the protein chain, inhibiting protein synthesis
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Adverse effects tetracyclines
Gi effects, nausea, vomitting, diarrhea, discolouration of teeth, diminished bone growth
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Tetracyclines use in special populations
strong affinity for calcium, therefore are used very cautiously during pregnancy or in children under 12
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Tetracyclines storage
can deteriorate into toxic degradation products id stored for long periods of time so it is important to discard outdated supplies
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Macrolides
- active against several bacterial infection cause by gram-positive microorganisms
-when an individual is allergic to penicillin, a macrolide may be an effective alternative
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Erythromycin
a type of macrolide effective in treating infections cause by some gram - negative bacteria
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Macrolides bind
to the 50S ribosomal subunit on tRNA and block peptide bond formation
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adverse effects of macrolides
-nausea
-vomiting
-diarrhea (most common after discontinuing erythromycin)
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antifolates
inhibitors of folate metabolism in bacteria
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tetrahydrofolic acid
a folate,
- is essential for bacteria to synthezise DNA and protein
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if tetrahydrofolic acid is not formed...
bacterial growth will slow
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2 examples of antifolate drugs
sulfoamides and trimethoprim
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sulfoamides
sulfamethoxazole, a member of the sulfoamide group, competitively inhibits the synthesis of tetrahydrofolic acid, by inhibiting para-aminobenzoic acid (PABA) incorporation into dihydropteroic acid
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how are sulfoamides selectivly toxic to bacteria
susceptible bacteria must synthesize tetrahydrofolic acid from PABA, however, mammalian cells use preformed tetrahydrofolic acid from surroundings
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Trimethoprim
inhibits the enzyme dihydrofolic acid reductase, inhibiting tetrahydrofolic acid formation
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how is trimethoprim selectively toxic to bacteria
because it has greater inhibitory actions on the bacterial enzyme than the human enzyme
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Combination antifolates
sulfamethoxazole-trimethoprim (AKA co-trimoxazole)
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what happens when inhibiting sequential steps in the metabolic pathway
a synergistic antibacterial effect is produced, a combination biproduct containing sulfamethoxazole and trimethoprim was developed
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what is co-trimoxazole useful in treating
UTIs, respiratory tract infections, and GI tract infections
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Antibiotic Combinations used for
- therapy of severe infection (where bacteria responsible is unknown or very dangerous)
-treatment of mixed bacterial infection where no single would eliminate all
-treat tuberculosis
-infections treated by two antibiotics that act synergistically
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disadvantages of antibiotic combinations
-unnecessary additional cost if single is effective
-increase risk of toxicicity
-increased opporitunity for resistant bacteria to arise when the combination is ineffective
-decrease # normal population of different bacteria
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Antimicrobial resistance
during replication, bacteria can mutate and evolve to have different properties, and can therefore become resistant to antibiotics
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Projeted deaths by 2050 due to antimicrobial resistance
50 million
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two factors associated with the development of antibiotic resistance
evolution of bacteria and clinical/environmental factors
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how does antibiotic resistance develop
1)Initial Population
2)add antibiotic to population
3)effects of antibiotic but some bacteria have traits resistant already
4)resistant bacteria replicate forming a new population and trait will become common to entire population
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3 main causes of antibiotic resitance
1. Over-prescription
2. Inappropriate use
3. Use in agriculture
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over prescription
physicians over prescribe, for many reasons, such as lack of diagnostic equipment or pressure fomr drug companies/patients
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Innapropriate use of antibiotics
ex. premature discontination, or sale of over the counter antibiotics
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antibiotic use in agriculture contributing to over prescription
may expose the animals to an unnecessary antibiotic which increases risk of drug-resistance development
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common misconception about the flu
that antibiotics will fight the flu and colds
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why will antibiotics not fight the flu or common colds
they are viruses not bacterial infections
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side effects of taking antibiotics when you dont need them
nausea, dizzy, diarrhea, yeast infections, C.diff
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reason for antibiotic resistance in E. coli
since the mcr-1 gene was first identified in pigs, it is likely this case of antibiotic resistance developed due to use of antibiotics in agriculture
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Four basic mechasisms how organisms acquire resistance to antibiotics
1. Uptake
2. Target
3. Inactivation
4. Efflux pumps
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Uptake leading to resistance
small molecules gaina ccess to the inside of the microorganism by moving through pores in the membranes. Mutation or lack of these makes organism resistant
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target leading to resistance
a mutation in the target for the antibiotic can reduce the binding of a drug to its target and be ineffective
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inactivation leading to resistance
Microorganisms develop an enzyme that inactivates the antibiotic (ex. penicillinase)
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efflux pumps leading to resistance
some microorganisms will over express transporters that pump the drug out of the microorganism before the cell can be injured
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antifungal drugs
only a few highly effective antifungal drugs are available
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two common classes of antifungal drugs
1. Echinocandins
2. Imidzoles (Azoles)
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types of Echinocandins
Cell wall inhibitors
- Micafungin
- Caspofungin
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Imidzoles (Azoles)
Ergosterol Synthesis Inhibitors
- Ketoconzole
-Fluconazole
-Miconazole
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Echinocandins
- newer class of antifungal drugs
- act by inhibiting synthesis of a component of the cell wall, resulting in disrupted of cell wall and fungal death
- well tolerated
- only available via IV
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Azoles
- are effective when taken orally or IV for systemic fungal infections
-all inhibit a fungal cytochrome P450, inhibiting ergosterol synthesis (critical for cell wall function and survival)
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selective toxicity of Azoles
- higher affinity for the fungal P450 than the human P450s that are involved in drug metabolism
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use of azoles
a number are available for over the counter drug treatment of yeast infections
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why dont azoles interfere with metabolism of drugs when taken as antifungals
higher affininty for p450 than the human P450s that are involved in drug metabolism
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what is a virus
a small infectious agent that is only able to multiply within the living cells of other animals, plants and bacteria
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are viruses specific in types of cells they infect
yes - dependant on cell receptors
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6 steps of virus life cycle
1. Attachment
2. Entry
3. Replication
4. Biosynthesis
5. Assemble
6. Release
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at which stage do msot anti viral drugs work
prevent replication
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two types of antivirals
1. Oseltamivir (Tamiflu)
2. Acyclovir
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Oseltamivir (Tamiflu)
-neuraminidase inhibitor used to treat influenza.
- prevent neighbouring cells from being infected with the virus
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Acyclovir
-taken up into infected cells and the virus activates acyclovir to the active form
-this inhibits viral DNA replication
-selective for cells infected with the virus
- drug of choice for treatment of serious infections caused by HSV
-also useful in combatting infections due to VSV (chickenpox/shingles)
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what is neuraminidase
an enzyme that allows spread of the virus from cell to cell
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long term use of acyclovir
decrease the frequency of recurrence of genital herpes
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major difference between antivirals and vaccines
their mechanism of actions
vaccines introduce nonfuncctional fragments prior to viral infections, and they are PREVENTATIVE, whereas antivirals treat infections already occurring in the body
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estrodiol and progesterone levels at begininning of cycle and endometrium (MENSTRUATION)
low and endometrium is sloughed
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what does the hypothalamus secrete in response to low levels of estrogen and progesterone
gonadotropin releasing hormone
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what does the gonadotropin releasing hormone do
stimulates the pituitary gland to release two gonadotropins: follicule stimulating hormone and lutenizing hormone
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in response to follicle stimualting hormone...
a number of ovarian follicles, eaching containing one egg (Ovum), begin to enlarge
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5-6 days after menstruation
a follicle begins to develop rapidly while others regress
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what does the mature folllicle secrete
estridiol, small amounts at first then larger, causing endometrium to thicken
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day 14 of cycle
- levels of estrogen and follicule stimulating homone peak
- levels of lutenizing hormone secretion peaks, stimulatin mature ovarian follicule to grow more rapidly
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what happens when follicule swells and bursts
releases ovum
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what is the first stage called (till day 14)
follicular phase
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what is the corpus luteum
ovarian follicle after it has burst and release ovum
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what does corpus luteum release
progesterone, stimulating endometrium to secrete nutrients
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wha tis progesterone
hormone supporting endometrium in second half of cycle (days 14-28)
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what happens if no fertilized ovum
after 10-12 days the corpus luteum caeses to function, progesterone secretion diminishes and endometrium loses hormonal support, leading to sloughing of the endometrium
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what is the second phase known as
luteal phase
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3 main effects of hormonal contraceptives
1. Inhibit hormone release
2. Inhibit Sperm migration
3. Inhibit ovum implantation
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How do hormonal contraceptives inhibit hormone release
- inhibit release of gonadotrophin-releasing hormone from the hypothalamus
-as a result, the pituitary is not stimulated to release follicule stimulating hormone and lutenizing hormone, therefore no follicular maturation or ovulation
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how do hormonal contraceptives inibit sperm migration
- commonly inclue progestins
-these alter secretion of endocervical gland to a scant, thick fluid not optimal for sperm migration
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what are progestins
progesterone-like compounds
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how do hormonal contraceptives inhibit ovum implantation
cause endometrium to not fully develop, making it unsuitable for implantation of fertilized ovum
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types of hormonal contraceptives
- oral
-depo-provera
-IUD
-transdermal patch
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oral contraceptives
-generally contain estrogen and progestin
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types of oral contraceptives
- fixed combination
-multiphasic
-progestin only pill
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fixed combination oral contraceptives
- fixe combination of estrogen and progestin
-21/28 days
-if taken for 28 days, mentstruation is eliminated
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when was the first foxed combination pill
1961
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Multiphasic oral contraceptives
- contain fixed estrogen and variable progestin
- progestin increases from week to week
-hormone dose kept to minimum, reduced adverse effects compared to fixed combination
-hormonal sequence mimics pattern of normal ovarian cycle
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Progestin only pill
aka mini-pill
- low doses of progestin
-acceptability less than with the estrogen-progestin combinations
-break thru bleeding often a problem
-slightly less efficacy
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Mild adverse effects of oral contraceptives
-nausea (caused by estrogen)
-edema (progestin and estrogen cause water retention)
-headache
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Moderate adverse effects of oral contraceptives
-break thru bleeding
-weight gain
-increased skin pigmentation (due to estrogen)
- acne (preogestin)
-hirsutism (hair growth on face and body from progestin)
-vaginal and uterine infections
-post drug amenorrhea
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Serious adverse effects of oral contraceptives
- Blood clots
-Heart attack
-Stroke
Hypertension
-Cancer
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why does oral contraceptives cause blood clots
estrogens induce the production of some of the factors required for blood coagulation, low incidence
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why does oral contraceptive increase risk of heart attack
estrogen-progestin oral contraceptives, risk if greater if patient is obease/smokes (associated with progestin)
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why does oral contraceptive increase stroke
increased risk for cerebrovascular disease, esp if over 35
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why does oral contraceptive increase hypertension
cardiovascular disease is more prevalent
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oral contraceptives and cancer
decrease ovarian and endometial cancer
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non-contraceotive benefits of oral contraceptives
- reduce risk of ovarian cysts
-reduce risk of ovarian and endometrial cancer
-reduced incidence of ectopic pregnancy
- less iron deficiency anemia
-lighter menstrual flow
-less acne and hirsutism (newer progestins)
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DEPOT
-slow-release formulation contraceptive injection
-progestin dose is injected intramuscularly every three months
progestin only
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adverse effects of DEPOT
-similar to mini pill
-breakthru bleeding
-alter profile of plasma lipids
-increase low density lipoproteins and decrease high density lipoproteins
-causing small increase coronary vascular disease
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Intrauterine Devices
implanted into the uterus by a medical professional
-most common type releases levongestrel
-some effective up to 8 yrs
-progeestin only
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when is a IUD a good option
people who wish to have long term reversible contraception and where estrogen is contraindicated
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adverse effects with IUD
- heavy menstrual flow after insertion
-pelvic discomfort
-increased UTIs
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Transdermal Patch
-contain estrogen and progestin applied to skin
-delivered at a constant rate for 7 days
-three patches per cycle
MOA same as estrogen-progestin oral contraceptives
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PROS oral contraceptives (enteral)
-most convienent
-least expensive
-non invasive
-self administered
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CONS oral contraceptives (enteral)
-variable absorption between patients due to differences in intestinal motility
-subject to first pass effect
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PROS paraenteral (intramuscular) the shot
- patients dont control dose
-delivers steady supply for set period
-avoids first pass effect
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CONS paraenteral (intramuscular) the sho
- volume is limited
-more invasive
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PROS of the patch (topical)
-convienent
-delivers steady supply for set period
-avoids first pass effect
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CONS the patch (topical)
-expensive
-local irritation
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what form of administration is IUD
urogenital
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Oral estrogin Progestin perfect use effectiveness vs Typical rate
99.7%:92%
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Patch perfect use effectiveness vs Typical rate
99.7%:92%
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Progestin only perfect use effectiveness vs Typical rate
98%:92%
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DEPO perfect use effectiveness vs Typical rate
99.7%:97%
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IUD perfect use effectiveness vs Typical rate
99.9%:99.9%
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Male Contraceptives
-taken orally or injected
-not yet reached canadian market
-attempts to inhibit spermatogensis have been successful
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Follicle stimulating hormone in males
stimualtes the seminiferous tubules in the testes to produce sperm
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Lutenizing hormone in males
stimulates the Lyedig cells to produce testosterone
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whewre are Lyedig cells found
adjacent to the seminiferous tubules in the testes
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tesosterone
hormone responsible for male secondary sex characteristics and inhibits hypothalamus from release for gonadotropin releasing hormone, preventing over production of testosterone
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attempts to create male contraceptives
inhibiting release of gonadotropin releasing hormone, thus, spermatogensis also decrease testosterone production leading to adverse effect of a descrese in sex drive
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Spermatogenesis
Hypothalamus> anterior pituitary via gonadal releaseing hormone
Anterior Pituitary> Seminiferous Tubules via FSH
Anterior Pituitary> Lyedig cells via LH
Seminiferous tubules> sperm
Lyedig cells> Testosterone
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Four main Compounds have been tested for use as male contraceptives, what are they
1. Androgen based
2. Estrogens
3. Progestin and androgen
4. Gossypol
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Androgen based male contraceptives
- inhibit release of GnRH and therefore spermatogenesis
- injected intramuscularly
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two major problems of androgen based male contracpetives
1. only 8-% responses with lower sperm count (<4mil)
2. Excess androgen enhanced the secondary sex characteristics including aggression
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Estrogens as male contraceptives
-suppress GnRH release and spermatogensis
-testosterone production decreases, as does sex drive, and men develop feminine characteristics
-subjects were infertile
-lost sex drive
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how did they overcome deleterious effects of estrogen on secondary sex characteristics
-small amounts of androgens were added to the regimen
-only 60% subjects became infetile and adverse effects were too numerous
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Progestin and androgen as male contraceptives
- synthetic progestin used to inhibit release of GnRH
loss spermatogenesis and testosterone production
-decreases male secondary sex characteristics
- androgen is added to release los testosterone
-shown more promise than other methods
-challenge to find good dose
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Gossypol as a male contraceptive
-cmpd obtained from cottonseed
-destroys elements of seminiferous tubules decreasing sperm production
-does not alter sex drive or other functions of testosterone
-extensive clinical trials in china
-infirtile sperm in 99%
-recovery not guaranteed
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major problem reported with gossypol
hypokalemia (low potassium), resulting in transient paralysis
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